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Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin.
- Source :
-
The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2004 Nov; Vol. 89 (11), pp. 5535-41. - Publication Year :
- 2004
-
Abstract
- Several properties of pancreatic beta-cells in type 2 diabetes (T2D) were studied by using islets isolated from T2D subjects. Moreover, because metformin has protective effects on nondiabetic beta-cells exposed to high glucose or free fatty acid levels, we investigated its direct action on T2D islet cells. Diabetic islets were characterized by reduced insulin content, decreased amount of mature insulin granules, impaired glucose-induced insulin secretion, reduced insulin mRNA expression, and increased apoptosis with enhanced caspase-3 and -8 activity. These alterations were associated with increased oxidative stress, as shown by higher nitrotyrosine concentrations, increased expression of protein kinase C-beta2 and nicotinamide adenine dinucleotide phosphate reduced-oxidase, and changes in mRNA expression of manganese- superoxide dismutase, Cu/Zn-superoxide dismutase, catalase, and glutathione peroxidase. Twenty-four-hour incubation of T2D islets with metformin was associated with increased insulin content, increased number and density of mature insulin granules, improved glucose-induced insulin release, and increased insulin mRNA expression. Moreover, apoptosis was reduced, with concomitant decrease of caspase-3 and -8 activity. These changes were accompanied by reduction or normalization of several markers of oxidative stress. Thus, T2D islets have several functional and survival defects, which can be ameliorated by metformin; the beneficial effects of the drug are mediated, at least in part, by a reduction of oxidative stress.
- Subjects :
- Aged
Cell Survival drug effects
Diabetes Mellitus, Type 2 physiopathology
Humans
Islets of Langerhans physiopathology
Metformin pharmacology
Middle Aged
Oxidative Stress drug effects
RNA, Messenger analysis
Reactive Oxygen Species
Reverse Transcriptase Polymerase Chain Reaction
Apoptosis drug effects
Diabetes Mellitus, Type 2 drug therapy
Hypoglycemic Agents therapeutic use
Islets of Langerhans drug effects
Metformin therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 0021-972X
- Volume :
- 89
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- The Journal of clinical endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 15531508
- Full Text :
- https://doi.org/10.1210/jc.2004-0150